Pineal and Retinal Serotonin N-Acetyltransferase Activity: Modulation by Phosphate

Abstract: Serotonin N -acetytransferase (NAT) activity in chicken pineal homogenates is increased 16-fold in the presence of high-molarity phosphate buffer (0.35 m ) as compared with its activity in low-molarity (0.05 m ) phosphate buffer. This phosphate effect on NAT does not depend on ionic, osmotic, or pH changes; rather, it appears to be a direct effect of phosphate on NAT activity. Phosphate also stabilizes NAT activity to thermal inactivation and inactivation caused by incubation at 4°C for 48 h. Stimulation of NAT activity by phosphate occurs only in chick pineal and retina, not in chick cerebrum, cerebellum or liver, nor in rat pineal or other tissues tested. There is a correlation between the occurrence of the phosphate effect and the occurrence of endogenous NAT circadian rhythmicity and light inactivation. The effect of phosphate on NAT activity in homogenates may reflect physiological mechanisms of NAT regulation.     

Higher Media Multi-Tasking Activity Is Associated with Smaller Gray-Matter Density in the Anterior Cingulate Cortex

Media multitasking, or the concurrent consumption of multiple media forms, is increasingly prevalent in today’s society and has been associated with negative psychosocial and cognitive impacts. Individuals who engage in heavier media-multitasking are found to perform worse on cognitive control tasks and exhibit more socio-emotional difficulties. However, the neural processes associated with media multi-tasking remain unexplored. The present study investigated relationships between media multitasking activity and brain structure. Research has demonstrated that brain structure can be altered upon prolonged exposure to novel environments and experience. Thus, we expected differential engagements in media multitasking to correlate with brain structure variability. This was confirmed via Voxel-Based Morphometry (VBM) analyses: Individuals with higher Media Multitasking Index (MMI) scores had smaller gray matter density in the anterior cingulate cortex (ACC). Functional connectivity between this ACC region and the precuneus was negatively associated with MMI. Our findings suggest a possible structural correlate for the observed decreased cognitive control performance and socio-emotional regulation in heavy media-multitaskers. While the cross-sectional nature of our study does not allow us to specify the direction of causality, our results brought to light novel associations between individual media multitasking behaviors and ACC structure differences.     

rTMS of the Left Dorsolateral Prefrontal Cortex Modulates Dopamine Release in the Ipsilateral Anterior Cingulate Cortex and Orbitofrontal Cortex

Background

Brain dopamine is implicated in the regulation of movement, attention, reward and learning and plays an important role in Parkinson''s disease, schizophrenia and drug addiction. Animal experiments have demonstrated that brain stimulation is able to induce significant dopaminergic changes in extrastriatal areas. Given the up-growing interest of non-invasive brain stimulation as potential tool for treatment of neurological and psychiatric disorders, it would be critical to investigate dopaminergic functional interactions in the prefrontal cortex and more in particular the effect of dorsolateral prefrontal cortex (DLPFC) (areas 9/46) stimulation on prefrontal dopamine (DA).

Methodology/Principal Findings

Healthy volunteers were studied with a high-affinity DA D2-receptor radioligand, [¹¹C]FLB 457-PET following 10 Hz repetitive transcranial magnetic stimulation (rTMS) of the left and right DLPFC. rTMS on the left DLPFC induced a significant reduction in [¹¹C]FLB 457 binding potential (BP) in the ipsilateral subgenual anterior cingulate cortex (ACC) (BA 25/12), pregenual ACC (BA 32) and medial orbitofrontal cortex (BA 11). There were no significant changes in [¹¹C]FLB 457 BP following right DLPFC rTMS.

Conclusions/Significance

To our knowledge, this is the first study to provide evidence of extrastriatal DA modulation following acute rTMS of DLPFC with its effect limited to the specific areas of medial prefrontal cortex. [¹¹C]FLB 457-PET combined with rTMS may allow to explore the neurochemical functions of specific cortical neural networks and help to identify the neurobiological effects of TMS for the treatment of different neurological and psychiatric diseases.     

Neurochemical Characterization of Extracellular Serotonin in the Rostral Ventromedial Medulla and Its Modulation by Noxious Stimuli

Abstract: Using in vivo microdialysis, we have characterized serotonin release from the rostral ventromedial medulla of the freely moving rat. Addition of tetrodotoxin or removal of calcium from the dialysis solution diminished the dialysate serotonin content, suggesting that spontaneous, calcium channel- and sodium channel-dependent neuronal release mechanisms contribute to the extracellular serotonin collected from the rostral ventromedial medulla. Extracellular serotonin concentration was increased by depolarization (with 100 m M potassium) and by the local administration of either a reuptake blocker (citalopram), a monoamine oxidase inhibitor (pargyline), or amphetamine. Serotonin release was reduced significantly by 8-hydroxy-2-(di- n -propylamino)tetralin, suggesting that serotonin_1A receptors may regulate release from rostral ventromedial medulla neurons. Because the basal serotonin concentration in the rostral ventromedial medulla was approximately twofold higher than that collected from the rostral ventrolateral medulla, a region that contains serotonin terminals but many fewer cell bodies, the possibility of release of serotonin from rostral ventromedial medulla neurons is discussed. Finally, intraplantar formalin injection significantly increased serotonin release, suggesting that this neurotransmitter contributes to nociceptive modulation by regulating the outflow of the rostral ventromedial medulla neurons.     

Functional Connectivity of the Caudal Anterior Cingulate Cortex Is Decreased in Autism

The anterior cingulate cortex (ACC) is frequently reported to have functionally distinct sub-regions that play key roles in different intrinsic networks. However, the contribution of the ACC, which is connected to several cortical areas and the limbic system, to autism is not clearly understood, although it may be involved in dysfunctions across several distinct but related functional domains. By comparing resting-state fMRI data from persons with autism and healthy controls, we sought to identify the abnormalities in the functional connectivity (FC) of ACC sub-regions in autism. The analyses found autism-related reductions in FC between the left caudal ACC and the right rolandic operculum, insula, postcentral gyrus, superior temporal gyrus, and the middle temporal gyrus. The FC (z-scores) between the left caudal ACC and the right insula was negatively correlated with the Stereotyped Behaviors and Restricted Interests scores of the autism group. These findings suggest that the caudal ACC is recruited selectively in the pathomechanism of autism.     

Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex

Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.     

Spatiotemporal Spike Coding of Behavioral Adaptation in the Dorsal Anterior Cingulate Cortex

The frontal cortex controls behavioral adaptation in environments governed by complex rules. Many studies have established the relevance of firing rate modulation after informative events signaling whether and how to update the behavioral policy. However, whether the spatiotemporal features of these neuronal activities contribute to encoding imminent behavioral updates remains unclear. We investigated this issue in the dorsal anterior cingulate cortex (dACC) of monkeys while they adapted their behavior based on their memory of feedback from past choices. We analyzed spike trains of both single units and pairs of simultaneously recorded neurons using an algorithm that emulates different biologically plausible decoding circuits. This method permits the assessment of the performance of both spike-count and spike-timing sensitive decoders. In response to the feedback, single neurons emitted stereotypical spike trains whose temporal structure identified informative events with higher accuracy than mere spike count. The optimal decoding time scale was in the range of 70–200 ms, which is significantly shorter than the memory time scale required by the behavioral task. Importantly, the temporal spiking patterns of single units were predictive of the monkeys’ behavioral response time. Furthermore, some features of these spiking patterns often varied between jointly recorded neurons. All together, our results suggest that dACC drives behavioral adaptation through complex spatiotemporal spike coding. They also indicate that downstream networks, which decode dACC feedback signals, are unlikely to act as mere neural integrators.     

Dysfunctional Noise Cancelling of the Rostral Anterior Cingulate Cortex in Tinnitus Patients

Background

Peripheral auditory deafferentation and central compensation have been regarded as the main culprits of tinnitus generation. However, patient-to-patient discrepancy in the range of the percentage of daytime in which tinnitus is perceived (tinnitus awareness percentage, 0 – 100%), is not fully explicable only by peripheral deafferentation, considering that the deafferentation is a stable persisting phenomenon but tinnitus is intermittently perceived in most patients. Consequently, the involvement of a dysfunctional noise cancellation mechanism has recently been suggested with regard to the individual differences in reported tinnitus awareness. By correlating the tinnitus awareness percentage with resting-state source-localized electroencephalography findings, we may be able to retrieve the cortical area that is negatively correlated with tinnitus awareness percentage, and then the area may be regarded as the core of the noise cancelling system that is defective in patients with tinnitus.

Methods and Findings

Using resting-state cortical oscillation, we investigated 80 tinnitus patients by correlating the tinnitus awareness percentage with their source-localized cortical oscillatory activity and functional connectivity. The activity of bilateral rostral anterior cingulate cortices (ACCs), left dorsal- and pregenual ACCs for the delta band, bilateral rostral/pregenual/subgenual ACCs for the theta band, and left rostral/pregenual ACC for the beta 1 band displayed significantly negative correlations with tinnitus awareness percentage. Also, the connectivity between the left primary auditory cortex (A1) and the rostral ACC, as well as between the left A1 and the subgenual ACC for the beta 1 band, were negatively correlated with tinnitus awareness percentage.

Conclusions

These results may designate the role of the rostral ACC as the core of the descending noise cancellation system, and thus dysfunction of the rostral ACC may result in perception of tinnitus. The present study also opens a possibility of tinnitus modulation by neuromodulatory approaches targeting the rostral ACC.     

Acute Valproate Exposure Induces Sex-Specific Changes in Steroid Hormone Metabolism in the Cerebral Cortex of Juvenile Mice

Neurochemical Research - Valproic acid (VPA), an antiepileptic and mood stabilizer, modulates neurotransmission and gene expression by inhibiting histone deacetylase activity. It is reported that...     

Modulation of the Activity of Mycobacterium tuberculosis LipY by Its PE Domain

Mycobacterium tuberculosis harbors over 160 genes encoding PE/PPE proteins, several of which have roles in the pathogen’s virulence. A number of PE/PPE proteins are secreted via Type VII secretion systems known as the ESX secretion systems. One PE protein, LipY, has a triglyceride lipase domain in addition to its PE domain. LipY can regulate intracellular triglyceride levels and is also exported to the cell wall by one of the ESX family members, ESX-5. Upon export, LipY’s PE domain is removed by proteolytic cleavage. Studies using cells and crude extracts suggest that LipY’s PE domain not only directs its secretion by ESX-5, but also functions to inhibit its enzymatic activity. Here, we attempt to further elucidate the role of LipY’s PE domain in the regulation of its enzymatic activity. First, we established an improved purification method for several LipY variants using detergent micelles. We then used enzymatic assays to confirm that the PE domain down-regulates LipY activity. The PE domain must be attached to LipY in order to effectively inhibit it. Finally, we determined that full length LipY and the mature lipase lacking the PE domain (LipYΔPE) have similar melting temperatures. Based on our improved purification strategy and activity-based approach, we concluded that LipY’s PE domain down-regulates its enzymatic activity but does not impact the thermal stability of the enzyme.     

Gender-Dependent Modulation of Brain Monoamines and Anxiety-like Behaviors in Mice with Genetic Serotonin Transporter and BDNF Deficiencies

1. Brain-derived neurotrophic factor (BDNF) supports serotonergic neuronal development and our recent study found that heterozygous mice lacking one BDNF gene allele interbred with male serotonin transporter (SERT) knockout mice had greater reductions in brain tissue serotonin concentrations, greater increases in anxiety-like behaviors and greater ACTH responses to stress than found in the SERT knockout mice alone.2. We investigated here whether there might be gender differences in these consequences of combined SERT and BDNF deficiencies by extending the original studies to female mice, and also to an examination of the effects of ovariectomy and tamoxifen in these female mice, and of 21-day 17-β estradiol implantation to male mice.3. We found that unlike the male SERT×BDNF-deficient mice, female SERT×BDNF mice appeared protected by their gender in having significantly lesser reductions in serotonin concentrations in hypothalamus and other brain regions than males, relative to controls. Likewise, in the elevated plus maze, female SERT×BDNF-deficient mice demonstrated no increases in the anxiety-like behaviors previously found in males.4. Furthermore, female SERT×BDNF mice did not manifest the ∼40% reduction in the expression of TrkB receptors or the ∼30% reductions in dopamine and its metabolites that male SERT×BDNF did. After estradiol implantation in male SERT×BDNF mice, hypothalamic serotonin was significantly increased compared to vehicle-implanted mice. These findings support the hypothesis that estrogen may enhance BDNF function via its TrkB receptor, leading to alterations in the serotonin circuits, which modulate anxiety-like behaviors.5. This double-mutant mouse model contributes to the knowledge base that will help in understanding gene×gene×gender interactions in studies of SERT and BDNF gene polymorphisms in human genetic diseases such as anxiety disorders and depression.     

Effect of Activation and Blockade of Nitrergic Neurotransmission on Serotonin System Activity of the Rat Medial Prefrontal Cortex

Journal of Evolutionary Biochemistry and Physiology - Nitric oxide (NO) and serotonin play an important role in the functioning of the medial prefrontal cortex, but their interaction has been...     

Functional and Anatomical Connectivity Abnormalities in Cognitive Division of Anterior Cingulate Cortex in Schizophrenia

Introduction

Current pathophysiological theories of schizophrenia highlight the role of altered brain functional and anatomical connectivity. The cognitive division of anterior cingulate cortex (ACC-cd) is a commonly reported abnormal brain region in schizophrenia for its importance in cognitive control process. The aim of this study was to investigate the functional and anatomical connectivity of ACC-cd and its cognitive and clinical manifestation significance in schizophrenia by using the resting-state functional magnetic resonance imaging (fMRI) and the diffusion tensor imaging (DTI).

Methods

Thirty-three medicated schizophrenics and 30 well-matched health controls were recruited. Region-of-interest (ROI)-based resting-state functional connectivity analysis and Tract-Based Spatial Statistics (TBSS) were performed on 30 patients and 30 controls, and 24 patients and 29 controls, respectively. The Pearson correlation was performed between the imaging measures and the Stroop performance and scores of the Positive and Negative Syndrome Scale (PANSS), respectively.

Results

Patients with schizophrenia showed significantly abnormal in the functional connectivity and its hemispheric asymmetry of the ACC-cd with multiple brain areas, e.g., decreased positive connectivity with the bilateral putamen and caudate, increased negative connectivity with the left posterior cingulated cortex (PCC), increased asymmetry of connectivity strength with the contralateral inferior frontal gyrus (IFG). The FA of the right anterior cingulum was significantly decreased in patients group (p = 0.014). The abnormal functional and structural connectivity of ACC-cd were correlated with Stroop performance and the severity of the symptoms in patients.

Conclusions

Our results suggested that the abnormal connectivity of the ACC-cd might play a role in the cognitive impairment and clinical symptoms in schizophrenia.     

The Neural Correlates of Mindful Awareness: A Possible Buffering Effect on Anxiety-Related Reduction in Subgenual Anterior Cingulate Cortex Activity

Background

Human personality consists of two fundamental elements character and temperament. Character allays automatic and preconceptual emotional responses determined by temperament. However, the neurobiological basis of character and its interplay with temperament remain elusive. Here, we examined character-temperament interplay and explored the neural basis of character, with a particular focus on the subgenual anterior cingulate cortex extending to a ventromedial portion of the prefrontal cortex (sgACC/vmPFC).

Methods

Resting brain glucose metabolism (GM) was measured using [¹⁸F] fluorodeoxyglucose positron emission tomography in 140 healthy adults. Personality traits were assessed using the Temperament and Character Inventory. Regions of interest (ROI) analysis and whole-brain analysis were performed to examine a combination effect of temperament and character on the sgACC/vmPFC and to explore the neural correlates of character, respectively.

Results

Harm avoidance (HA), a temperament trait (i.e., depressive, anxious, vulnerable), showed a significant negative impact on the sgACC/vmPFC GM, whereas self-transcendence (ST), a character trait (i.e., intuitive, judicious, spiritual), exhibited a significant positive effect on GM in the same region (HA β = −0.248, p = 0.003; ST: β = 0.250, p = 0.003). In addition, when coupled with strong ST, individuals with strong HA maintained the sgACC/vmPFC GM level comparable to the level of those with low scores on both HA and ST. Furthermore, exploratory whole-brain analysis revealed a significant positive relationship between ST and sgACC/vmPFC GM (peak voxel at x = −8, y = 32, z = −8, k = 423, Z = 4.41, corrected p ^FDR = 0.030).

Conclusion

The current findings indicate that the sgACC/vmPFC might play a critical role in mindful awareness to something beyond as well as in emotional regulation. Developing a sense of mindfulness may temper exaggerated emotional responses in individuals with a risk for or having anxiety and depressive disorders.     

Fluoxetine Increases Extracellular Dopamine in the Prefrontal Cortex by a Mechanism Not Dependent on Serotonin

Fluoxetine at 10 and 25 mg/kg increased (167 and 205%, respectively) the extracellular dopamine concentration in the prefrontal cortex, whereas 25 (but not 10) mg/kg citalopram raised (216%) dialysate dopamine. No compound modified dialysate dopamine in the nucleus accumbens. The effect of 25 mg/kg of both compounds on cortical extracellular dopamine was not significantly affected by 300 mg/kg p-chlorophenylalanine (PCPA) (fluoxetine, saline, 235%; PCPA, 230%; citalopram, saline, 179%; PCPA, 181%). PCPA depleted tissue and dialysate serotonin by approximately 90 and 50%, respectively, and prevented the effect of fluoxetine and citalopram on dialysate serotonin (fluoxetine, saline, 246%; PCPA, 110%; citalopram, saline, 155%; PCPA, 96%). Citalopram significantly raised extracellular serotonin from 0.1 to 100 microM (251-520%), whereas only 10 and 100 microM increased dialysate dopamine (143-231%). Fluoxetine similarly increased extracellular serotonin (98-336%) and dopamine (117-318%). PCPA significantly reduced basal serotonin and the effects of 100 microM fluoxetine (saline, 272%; PCPA, 203%) and citalopram (saline, 345%; PCPA, 258%) on dialysate serotonin but did not modify their effect on dopamine (fluoxetine, saline, 220%; PCPA, 202%; citalopram, saline, 191%; PCPA, 211%). The results clearly show that the effects of fluoxetine and of high concentrations of citalopram on extracellular dopamine do not depend on their effects on serotonin.